Non-steroidal anti-inflammatory drugs (NSAIDs) form a very large category of drugs that are primarily used to reduce fever, pain and inflammation. As the name implies, they do not act via the same path as steroids that suppress the immune system from producing fever and pain. NSAIDs are also non-narcotic and their sub-categories are based on their chemical structure. They differ in not only form, but also which enzymes they inhibit and for how long.
Among the ‘Salicylates’ sub-category, the most famous drug is aspirin known to be an effective pain killer. It also has other therapeutic uses such as effective blood thinner. Other known drugs in this sub-category are salicylamide, salicyl salicylate, methyl salicylate, magnesium salicylate, faislamine, ethenzamide, diflunisal, choline magnesium salicylate, benorylate/benorilatem and amoxiprin.
Another sub-category is constituted by ‘Arylalkanoic acids’, which has an aryl group on one of the rings of the drug molecule. The drugs in this sub-category presently in use are aceclofenac, acemetacin, alclofenac, bromfenac, diclofenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, and tolmetin.
The ‘2-Arylpropionic acids’ are an important sub-category and tends to have an ending of ‘profen’ in their generic names. The known drugs in this sub-category are alminoprofen, benoxaprofen carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid.
Another sub-category of NSAIDs is collectively known as ‘N-Arylanthranilic acids’; the generic drugs in this sub-category tend to have ending of ‘fenamic acids’ and the well known drugs are mefenamic acid, flufenamic acid, meclofenamic acid, and tolfenamic acid.
‘Oxicams’ is yet another sub-category of NSAID, which are essentially enolic acid (e.g., a double bond between two adjacent carbon atoms and a hydroxyl containing molecules) that exhibit keto-enol tautomerism. The well known drugs in this sub-category are droxicam, lomoxicam, meloxicam, piroxicam, and tenoxicam.
Another sub-category is characterized as ‘Pyrazolidine’ derivates; pyrazolidine is a five member ring with two nitrogen atoms adjacent to each other that bear different functional groups. The well known drugs in this sub-category are ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone.
Finally, another important sub-category of NSAIDs is known as ‘COX-2 Inhibitor’ for their ability to inhibit COX-2 enzyme selectively which was considered clinically very significant. Selective NSAIDs (also called COX-2 inhibitors) are as effective in relieving pain and inflammation as nonselective NSAIDs but are less likely to cause gastrointestinal injury. Due to their decreased potential to cause ulcers or gastrointestinal bleeding, selective NSAIDS such as celecoxib are sometimes recommended for people who have had a peptic ulcer, gastrointestinal bleeding, or gastrointestinal upset when taking other nonselective NSAIDs. However, many of the drugs in this sub-category have been withdrawn from the US market in view of other observed side effects, which include valdecoxib, rofecoxib, parecoxib, etoricoxib. Lumiracoxib is known to have been put on watch list; the only drug in this sub-category available commercially is celecoxib. Numeslide, also a COX-2 inhibitor has been withdrawn in many countries due to adverse effects.
NSAIDs have strong anti-inflammatory, antipyretic, and analgesic properties, and are used for the treatment of a variety of acute and chronic conditions associated with pain, fever and inflammation. Some of the conditions that NSAIDs are widely used include rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, inflammatory arthropathies, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, pyrexia, ileus, renal colic, and in pain associated with injuries and dental procedures. The principal pharmacological effects of NSAIDs in reducing the pain and inflammation have been demonstrated to be due to their potential to inhibit enzymes, called cyclooxygenase, which in turn inhibit prostaglandin synthesis. Cyclooxygenase enzyme inhibition is also responsible for many of the side effects of NSAIDs. Two main types of NSAIDs are known as ‘selective’ and ‘nonselective’ depending on their ability to inhibit specific types of cyclooxygenase (COX) enzymes. Nonselective NSAIDs are known to inhibit both COX-1 and COX-2 enzymes whereas selective NSAIDs preferentially inhibit COX-2 enzymes found at the sites of inflammation more than the COX-1 enzymes normally found in the stomach, blood platelets and blood vessels.
Most nonselective NSAIDs, such as aspirin, ibuprofen, naproxen etc. are commonly available without prescription in most countries and belong to ‘Over-the-counter (OTC)’ group. Most people also tolerate NSAIDs without any problem when taken occasionally. However, side effects occur and are frequently encountered when the drugs are necessarily taken on long-term basis.
The clinical utility of NSAIDs is significantly limited due largely to their ability to cause a diverse array of toxicities, particularly of those in the gastrointestinal tract, renal, and cardiovascular systems. The most common side effects and associated risks of their use due to their toxicities include the following:
Gastrointestinal system: While short term use of NSAIDs can cause stomach upset (dyspepsia), their long term use, especially at high doses, can lead to peptic ulcer and bleeding of the upper gastrointestinal tract in the stomach. These side effects are caused by NSAIDs inhibiting the COX-1 enzyme resulting into decrease of mucous production in cells lining of the gastrointestinal tract, leaving it vulnerable to gastric acid, bile, enzymes, and alcohol. Gastrointestinal injuries range from heartburn, nausea, erosion and abdominal pain to serious complications such as ulcers and hemorrhage (Shoenfeld P, M O Kimmey, J. Scheiman, D. Bjorkman, L. Laine, Aliment Pharmacol Ther 1999; 13:1273-1285). COX-1 has been found to be responsible for protecting the stomach through mucous membrane and immune cell defense, maintaining blood flow and kidney function, and processing sensations.
Kidney Toxicity: A comprehensive review of nephro-toxicity of existing NSAIDs suggested that the adverse effects of NSAIDs are mediated via inhibition of prostaglandin synthesis from arachidonic acid by non-specific blocking of the enzyme cyclooxygenase leading to vasoconstriction and reversible mild renal impairment in volume contracted states. (Ejaz P, Bhojani K, Joshi V R; J. Assoc. Phys. India, Vol 52, 2004, pp 632-640) This could lead to acute tubular necrosis and acute renal failure when unopposed. In patients on long term NSAIDs without acute or chronic renal failure, subclinical renal dysfunction such as reduced creatinine clearance and impaired urine concentrating ability has been observed. This sub-clinical dysfunction, although reversible on withdrawal of NSAIDs in most cases, some cases of persistent residual dysfunction have also bean reported. The authors conclude that despite a wide range of NSAIDs being available, a renal safe NSAID is yet to be discovered.
It has been determined that use of COX-2 inhibitors increases the chances of having a heart attack. Further, most NSAIDs, including COX-2 inhibitors boost blood pressure and could counteract the effect of some blood-pressure drugs. They have also been shown to impair blood vessels' ability to relax and may stimulate the growth of smooth muscle cells inside arteries leading to clogging of arteries, a process known as atherosclerosis.
Other Toxicities: One of the other toxicities associated with the use of NSAIDs is the ‘Liver toxicity’; the long term use of NSAIDs, especially at high doses, is reported to harm the liver. Ringing in the ears (tinnitus) is another malady reported by many people on high doses of aspirin or other NSAIDs. Further, anyone who has a cardiovascular disease (i.e., coronary artery disease or angina) may have a further increase in risk of heart attacks when taking an NSAID other than aspirin which is sometimes recommended in low doses to people with coronary artery disease to reduce the risks of developing a blood clot.
Regimens of NSAID therapy, therefore, include administration of antacids (acid neutralization), and cimetidine, ranitidine and famotidine (acid secretion inhibition) as a matter of necessity as of now and the search for a better and safe composition of NSAID remains a challenge particularly where the therapy must be protracted for a long time, e.g., in treatment of rheumatoid arthritis in old people.